(3) Pharmacodynamics: Receptors III – Intracellular receptors

Intracellular receptor

receptor located inside the cell.

Intracellular Receptors

They commonly respond to…

lipophilic molecules:

• steroid hormones

• thyroid hormones

• retinoids

• vitamin D

• fatty acids

Intracellular Receptors

Why they commonly respond to lipophilic molecules:

Receptor is inside cell

→ ligand must cross the cell membrane

→ ligand generally needs lipophilic properties

Intracellular Receptors

Main job

Ligand enters cell

→ binds intracellular receptor

→ receptor interacts with DNA

→ gene expression changes

Intracellular receptors are…

 ligand-activated transcription factors.

 Intracellular Receptor Structure

• LBD = Ligand-Binding Domain

  • LBD → binds the ligand

• DBD = DNA-Binding Domain

  • DBD → binds DNA

    • contains 2 zinc fingers

    • helps the receptor recognize the correct DNA sequence

• Hinge region

  • Hinge → gives flexibility

📌 POWERPOINT DETAIL:

• AF-1 → ligand-independent activation

• AF-2 → ligand-dependent activation

Intracellular receptors

• onset?

• duration?

• onset - slow (Professor explained that effects may take days, rather than seconds or minutes)

• duration - long

Why Intracellular Receptors Act Slowly?

Intracellular receptor activated

→ gene expression changes

→ RNA made

→ protein made

→ biological response

This takes time.

Intracellular receptors directly or indirectly regulate gene expression?

Intracellular receptors directly regulate gene expression → no second messenger is required for this direct mechanism.

Type I vs Type II

	Type I	Type II
Starts where?	Cytoplasm	Nucleus
HSPs (Heat Shock Protein)	Yes	No cytoplasmic HSP step
Usually forms	Homodimer	Heterodimer with RXR (DNA/corepressor) → transcription suppressed
Examples	Steroid receptors	Thyroid, vitamin D, retinoic acid, PPARs

Type I Receptors

Mechanism

Before ligand:

Type I receptor in cytoplasm + heat shock proteins (HSPs)

Then:

Lipophilic ligand enters cell

→ binds receptor

→ receptor changes shape

→ HSPs dissociate

→ 2 same receptors come together = homodimer

→ homodimer enters nucleus

→ finds correct DNA sequence (HRE)

→ binds DNA

→ gene expression changes

HRE stands for…

Hormone Response Element

What is HRE — Hormone Response Element?

• HRE = specific DNA sequence where the activated receptor binds.

• Palindromic = reads the same in both directions.

Hormone Response Element

Gene expression can be:

• activated

• suppressed

Do not assume intracellular receptors always turn genes on.

shape/pattern of the DNA sequence that the receptor recognizes.

• Type I receptors →

• Type II receptors →

• Type I/steroid receptors → inverted-repeat/palindromic-type arrangement

• Type II receptors → direct-repeat elements

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Type 1 receptor example

Corticosteroid receptors - suppress gene expression.

Corticosteroid

→ intracellular receptor

→ receptor interacts with DNA

→ ↓ inflammatory cytokine gene expression

→ ↓ inflammatory cytokine production

→ ↓ inflammation

Type II receptor

Typical mechanism

Before ligand:

Type II receptor

• RXR

• DNA

• corepressor
  → transcription suppressed

Then:

Ligand enters nucleus

→ binds receptor

→ receptor changes shape

→ corepressor leaves

→ coactivator binds

→ gene expression changes

Main pathway

Ligand → nuclear Type II receptor → corepressor leaves → coactivator binds → gene expression changes

Heterodimer =

2 DIFFERENT receptors together

Corepressor →

Coactivator →

Corepressor → suppresses gene expression

Coactivator → helps activate gene expression

Both Type I and Type II receptors can ultimately…

activate or suppress genes depending on the gene being regulated.

What Triggers Receptor Activation?

Ligand binds

→ receptor changes shape

→ later receptor events occur

Orphan receptor

•  receptor discovered before its natural/endogenous ligand was known.

• We know the receptor → we do not yet know what naturally binds it

   

Adopted orphan receptor =

originally an orphan → natural ligand later discovered.

PPAR

• intracellular receptors (type 2) involved in metabolism/insulin resistance.

• PPAR ≠ insulin receptor.

Intracellular receptors may bind DNA as:

• homodimers

• heterodimers

• monomers

depending on the receptor class.

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Tell me about the the Thyroid Hormone Example

• Professor used thyroid hormone during development to show how important proper intracellular-receptor signaling is for normal development. so you can Normal hormone level, but abnormal receptor, which can cause abnormal response can still occur

A signaling problem can come from either:

the ligand/hormone

OR

the receptor

Professor's analogy:

Ligand = key

Receptor = lock

Both have to work correctly.

Tissue Specificity

• Same hormone, different cells respond differently because of -

• Receptor
  Cofactors
  Chromatin

Crosstalk

Signaling pathways can interact with each other.

Example discussed:

Intracellular receptor signaling ↔ tyrosine kinase signaling